Melanoma incidence continues to rise at an alarming rate. Attempts to improve survival in patients with melanoma have focused on melanoma prevention and the detection of melanoma at a surgically curable stage. The identification of high risk cohorts and a well characterized sequence of melanoma tumor progression provide a framework for developing chemoprevention studies of melanoma. Dysplastic nevi are clinically and histologically defined "intermediate" lesions that are potential precursors of melanoma and markers of melanoma risk. Epidemiologic studies identify two subsets of individuals with dysplastic nevi that are at sufficiently high frisk for melanoma to warrant attempts at chemoprevention; individuals with dysplastic nevi and a personal history of melanoma and individuals with dysplastic nevi from familial melanoma families. We propose to conduct a multicenter, randomized clinical study of topical tretinoin and 4-HPR (fenretinide) for the chemoprevention of melanoma in conjunction with the Eastern cooperative Oncology Group (ECOG). The study population is a cohort of individuals with large numbers of dysplastic nevi and a personal or family history of melanoma. The study utilizes morphologic and histologic changes in dysplastic nevi as the clinical endpoint. We will provide morphological, pathological, photographic, and informatics expertise to the study by; 1) coordinating and standardizing photography, b) providing computer digitization and archiving of clinical images and analysis of the pre and post treatment clinical photographs, and c) providing expert processing and histological analysis of the excised nevi. We hypothesize that pharmacologic treatment with 4-HPR and/or tretinoin will result in a clinical improvement in dysplastic nevi and that this clinical response will be associated with histologic evidence of decreased numbers of lesional cells. We propose to classify the mechanisms involved in effecting this clinical response by measuring in-situ expression of markers of nevomelanocyte apoptosis, cytolytic immune cells, and nevomelanocyte retinoid receptor expression at multiple time points of therapy.